U.S. patent number 7,022,687 [Application Number 10/089,436] was granted by the patent office on 2006-04-04 for combination of loteprednol and antihistamines.
This patent grant is currently assigned to Asta Medica AG. Invention is credited to Juergen Engel, Sabine Heer, Degenhard Marx, Istvan Szelenyl.
United States Patent |
7,022,687 |
Szelenyl , et al. |
April 4, 2006 |
Combination of loteprednol and antihistamines
Abstract
The present invention relates to a novel combination of a soft
steroid, in particular loteprednol, and at least one antihistamine,
such as, for example, azelastine and/or levocabastine, for
simultaneous, sequential or separate administration in the local
treatment of allergies and airway disorders, for example of
allergic rhinitis (rhinoconjunctivitis).
Inventors: |
Szelenyl; Istvan (Schwaig,
DE), Marx; Degenhard (Radebeul, DE), Heer;
Sabine (Radebeul, DE), Engel; Juergen (Alzenau,
DE) |
Assignee: |
Asta Medica AG (Dresden,
DE)
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Family
ID: |
7924100 |
Appl.
No.: |
10/089,436 |
Filed: |
September 26, 2000 |
PCT
Filed: |
September 26, 2000 |
PCT No.: |
PCT/EP00/09391 |
371(c)(1),(2),(4) Date: |
July 23, 2002 |
PCT
Pub. No.: |
WO01/22955 |
PCT
Pub. Date: |
April 05, 2001 |
Foreign Application Priority Data
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Sep 30, 1999 [DE] |
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199 47 234 |
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Current U.S.
Class: |
514/179; 514/330;
514/217.05 |
Current CPC
Class: |
A61K
31/56 (20130101); A61P 27/16 (20180101); A61K
45/06 (20130101); A61P 43/00 (20180101); A61P
37/08 (20180101); A61P 11/02 (20180101); A61P
27/14 (20180101); A61P 11/06 (20180101); A61P
29/00 (20180101); A61P 11/00 (20180101); A61K
31/56 (20130101); A61K 2300/00 (20130101) |
Current International
Class: |
A61K
31/56 (20060101); A61K 31/47 (20060101); A61K
31/55 (20060101) |
Field of
Search: |
;514/179,217.05,330 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0 709 099 |
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May 1996 |
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EP |
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WO 97/01337 |
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Jan 1997 |
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WO |
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Other References
Friedlaender, Current Opinion in Ophthalmology 1998, 9/4 54-58.
cited by examiner .
Isaac, Lancet, Worldwide variation in prevalence of symptoms of
asthma, allergic rhinoconjunctivitis, and atopic eczema, vol. 351,
pp. 1225-1332, Aug. 25, 1998. cited by other .
I. Annesi-Maesano et al., Revue Francaise d'Allergologie, "La
rhinite de l'adolescent Resultats de l'enquete ISAAG" vol. 38, pp.
283-289, 1998. cited by other .
Medline, E. Norman et al., European Journal of Allergy, "Prevalence
and incidence of asthma and rhinoconjunctivitis in Swedish
teenagers," vol. 53, pp. 28-35, 1998, abstract. cited by
other.
|
Primary Examiner: Cook; Rebecca
Attorney, Agent or Firm: Burns, Doane, Swecker & Mathis,
L.L.P.
Claims
What is claimed is:
1. A pharmaceutical composition comprising an effective amount of
loteprednol or a pharmaceutically acceptable ester thereof and an
effective amount of azelastine.
2. The composition according to claim 1, wherein the azelastine is
administrable nasally or ocularly.
3. The composition according to claim 1, wherein the
pharmaceutically tolerable ester is loteprednol etabonate.
4. A method for the treatment of one or more allergic disorders
selected from the group consisting of allergic rhinitis and
allergic conjunctivitis comprising administering to a person in
need thereof, an effective amount of loteprednol or a
pharmaceutically acceptable ester thereof and an effective amount
of intranasally or intraocularly administrable azelastine
optionally together with customary excipients or vehicles, for
simultaneous, sequential or separate administration.
5. A method for the treatment and prophylaxis of one or more
allergic disorders selected from the group consisting of allergic
rhinitis and allergic conjunctivitis, comprising administering to a
person in need thereof, an effective amount of loteprednol and an
effective amount of azelastine, wherein the loteprednol or a
pharmaceutically acceptable ester thereof and the azelastine is
administered simultaneously, sequentially or separately, optionally
together with customary excipients or vehicles.
6. The method according to claim 5, wherein the loteprednol is
administered as an inhalable liquid preparation.
7. The method according to claim 5, wherein the azelastine is
administered orally.
8. A method for the treatment of one or more allergic disorders
selected from the group consisting of allergic rhinitis and
allergic conjunctivitis comprising administering to a patient in
need thereof, a combination of an effective amount of loteprednol
or a pharmaceutically acceptable ester thereof and an effective
amount of azelastine for simultaneous, sequential or separate
administration.
9. The composition according to claim 1, wherein the daily dose of
loteprednol is between 10 and 500 .mu.g and the daily does of
azelastine is between 50 and 500 .mu.g.
10. The method according to any one of claims 4, 6 or 8 wherein the
daily dose of loteprednol is between 10 and 500 .mu.g, and the
daily dose of azelastine is between 50 and 500 .mu.g.
11. The method of claim 9, wherein the daily dose of loteprednol is
between 50 and 200 .mu.g and the daily does of azelastine is
between 100 and 200 .mu.g.
12. The method of claim 10, wherein the daily dose of loteprednol
is between 50 and 200 .mu.g and the daily does of azelastine is
between 100 and 200 .mu.g.
Description
This is a 371 of PCT/EP00/09391 filed Sep. 26, 2000.
The present invention relates to a novel combination of a soft
steroid, in particular loteprednol, and at least one antihistamine,
such as, for example, azelastine and/or levocabastine, for
simultaneous, sequential or separate administration in the local
treatment of allergies and airway disorders, for example of
allergic rhinitis or rhinoconjunctivitis.
BACKGROUND OF THE INVENTION
The number of allergic disorders is increasing greatly worldwide.
Studies have shown that on average 7.5% of all children and
adolescents worldwide suffer from rhinoconjunctivitis (hay fever
combined with an ocular symptomatology) (Worldwide variation in
prevalence of symptoms of asthma, allergic rhinoconjunctivitis and
atopic eczema: ISAAC, Lancet, 351, 1225-1332, 1998). In West
European countries, the prevalence, at about 14%, is markedly
higher (Annesi-Maesano I. and Oryszczyn MP.: Rhinitis in
adolescents, Results of the ISAAC survey, Revue Francaise
d'Allergologie et d'Immunologie Clinique, 38, 283-289, 1998; Norman
E., Nystrom L, Jonsson E and Stjernberg N: Prevalence and incidence
of asthma and rhinoconjunctivitis in Swedish teenagers, European
Journal of Allergy and Clinical Immunology, 53, 28-35, 1998).
Despite intensive research activity, the pathogenesis of
rhinoconjunctivitis has still not been completely clarified. Even
if marked advances in the medical treatment of this disorder have
been achieved in the past years, the therapy is still not
satisfactory. The acute symptoms (itching, reddening, swelling,
rhinorrhea and lacrimation) of rhinoconjunctivitis can be readily
controlled, inter alia with the aid of antihistamines. However,
they barely have a therapeutically relevant influence on the
inflammation which underlies the disorder and is always
progressive. Often, allergic rhinitis or rhinoconjunctivitis is
regarded both by patients and by the physician as a trivial
disorder and accordingly is only inadequately treated. As a result,
however, a so-called change of stage can occur, i.e. bronchial
asthma, which is to be taken very seriously, develops from the
relatively harmless rhinitis. For this reason, it is indispensable
to treat even allergic rhinoconjunctivitis adequately and
intensively. Only then can the patients live symptom-free and only
then can a change of stage, which under certain circumstances is
life-threatening, be prevented.
Frequently, it cannot be establised by the treating physician in
borderline cases with absolute certainty whether "only"
rhinoconjunctivitis is still present or whether an airway disorder,
such as bronchial asthma, is already present. It is advantageous if
the combination according to the invention can also be employed for
the treatment of disorders of the upper and lower airways.
At the present time, the corticosteroids are most effectively able
to control the inflammation underlying the rhinoconjunctivitis.
Many patients, but also physicians, however, do not employ these
medicaments at all or only very hesitantly, usually only in a late
phase of the disorder, because of their possible systemic side
effects (e.g. slowdown in growth, osteoporosis).
Loteprednol belongs to the so-called "soft" steroids. Unlike other
corticosteroids, which are usually only broken down in the liver to
give pharmacodynamically inactive metabolites, in the case of the
soft steroids the metabolic inactivation partly already takes place
at the site of their administration (intranasal, ocular or
intrapulmonary). As a result of this partial local metabolization,
no or only very little pharmacodynamically active substance reaches
the systemic blood circulation, so that the steroid-specific side
effects virtually do not have to be reckoned with. Loteprednol is
already licensed for the therapy of allergic conjunctivitis and
uveitis.
Antihistamines are employed in the acute phase of allergic
rhinoconjunctivitis for the alleviation of the often irritating
symptoms. The topical application of these medicaments is
particularly advantageous, as high local concentrations of the
active compound can be broken down in this way without having to
reckon with appreciable side effects. At the current time, two
locally administrable antihistamines, azelastine and levocabastine,
are on the market. Both are highly efficacious and very highly
tolerable.
Surprisingly, it has now been found that the novel combination of a
soft steroid and at least one antihistamine is advantageous in the
treatment of allergies and/or airway disorders by topical
administration. Administration can in this case be carried out
simultaneously, sequentially or separately. The invention serves to
improve the therapy of allergic rhinitis (rhinoconjunctivitis). The
antihistamine provides for the rapid elimination of the acute
symptoms (e.g. reddening, itching, swelling). Using the
corticosteroid contained in the combination, the inflammation
underlying the condition can be successfully controlled.
According to one embodiment of the invention, loteprednol and its
pharmaceutically acceptable esters, in particular loteprednol
etabonate, is a particularly suitable soft steroid. The preparation
of loteprednol and loteprednol etabonate is described, for example,
in German Patent No. DE 31 26 732, the corresponding U.S. Pat. No.
4,996,335 and the corresponding Japanese Patent No. JP-89 011
037.
Further suitable soft steroids according to the invention are
described, for example, in German Patent No. 37 86 174, the
corresponding European Patent No. EP 0 334 853 and the
corresponding U.S. Pat. No. 4,710,495.
Azelastine and levocabastine can also be used in the form of the
pharmaceutically tolerable salts. The hydrochlorides, for example,
are preferred.
By means of the topical administration of the components (steroid
and antihistamine), therapeutically efficacious concentrations can
be achieved even at low doses. The combined administration of both
substances (antihistamine+loteprednol) makes possible the control
of the troublesome early-phase reactions such as itching,
rhinorrhea by the antihistamine and the progress of the
inflammation by the loteprednol. Moreover, the danger of the
occurrence of undesired effects is thereby reduced to a minimum and
better compliance of the patients is thus to be expected.
The present invention describes a novel combination, in which a
soft steroid (preferably loteprednol) and an antihistamine
(preferably azelastine and/or levocabastine) are given topically
(intranasally or intraocularly) simultaneously, one after the other
as individual substances or as a fixed combination. As a result of
this combination, not only a rapid onset of action occurs but also
a high therapeutic efficacy is achieved, which is accompanied by a
strong antiinflammatory action. In one advantageous embodiment, the
active components of this combination are present in the form of a
fixed combination, owing to which the administration is simpler for
the patients, since both active compounds are contained in one and
the same container.
According to a further embodiment of the invention, the
antihistamine can also be administered orally.
The intended dosage is carried out twice daily, the individual dose
of the soft steroid (loteprednol) being between 10 and 500 .mu.g,
preferably 50 and 200 .mu.g. The dose of antihistamine is 50-500
.mu.g, preferably 100-200 .mu.g. The actual dose depends on the
general condition of the patients (age, weight, etc.) and the
degree of severity of the disorder.
The following pharmacological investigation was carried out in
order to support the invention described.
In vitro, investigations on the influencing of the release of the
proinflammatory cytokine TNF.alpha. in human blood of various
donors diluted 1:5 were carried out. The stimulation was effected
using lipopolysaccharide (LPS) from Salmonella abortus equi (10
.mu.g/ml) over the course of 24 h at 37.degree. C. and 5% CO.sub.2
in an incubator. The TNF.alpha. release was determined using an
ELISA, based on antibodies from Pharmingen. The results were
indicated as the percentage inhibition of the LPS-induced
TNF.alpha. release and are shown in Table 1.
TABLE-US-00001 TABLE 1 Concentration Inhibition of Active compound
(.mu.mol/l) TNF.alpha. release Azelastine 10 2% Loteprednol 0.001
1% 0.01 2% 0.03 8% Azelastine + 10 + 0.001 12%* loteprednol 10 +
0.01 18%* 10 + 0.03 22%* *significant (p < 0.05)
If the antihistamine azelastine or the soft steroid loteprednol is
administered alone, the LPS-induced TNF.alpha.release remains
virtually unchanged. In the presence of azelastine (10 .mu.mol/l)
the TNF.alpha. release is inhibited to an increased extent by
loteprednol in a concentration-dependent manner.
In vivo investigations were carried out on young domestic pigs
actively sensitized with an antigen (extract from Ascaris suum).
Three weeks later, they were exposed to allergen challenge, which
was carried out by intranasal instillation of the Ascaris extract.
This local intranasal allergen challenge leads to a very great
increase in the nasal secretion (rhinorrhea). The amount of
secretion was determined gravimetrically. The results are compiled
in Table 2.
TABLE-US-00002 TABLE 2 Active Dose in Inhibition of Number of
compound .mu.g/nostril nasal secretion animals Azelastine 10 15% 5
Loteprednol 20 8% 5 Azelastine + 10 + 20 48%* 5 loteprednol
*significant (p < 0.05)
If the antihistamine azelastine or the soft steroid loteprednol is
used at the dosages 10 or 20 .mu.g/nostril, only marginal
inhibition of the allergically induced nasal hypersecretion occurs.
If both active compounds are given at the same time, however, the
rhinorrhoea is (significantly) reduced by 48%.
Various pharmaceutical formulations, e.g. nasal sprays, nasal drops
and eye drops, are suitable for topical application.
The present invention describes a combination in which a soft
steroid, e.g. loteprednol, and an antihistamine, e.g. azelastine
and/or levocabastine, are administered simultaneously, one after
the other as individual substances or as a fixed combination.
On account of the water solubility of the active compound
azelastine hydrochloride, formulations containing this active
compound can preferably be formulated as solutions. Loteprednol
etabonate, however, is virtually water-insoluble and is therefore
formulated as an aqueous suspension. In a formulation in which both
active compounds are combined, azelastine hydrochloride is
accordingly present dissolved in water and loteprednol etabonate
suspended in water.
In addition to the active constituents antihistamine, e.g.
azelastine hydrochloride, and soft steroid, e.g. loteprednol
etabonate, the pharmaceutical preparations according to the
invention can contain further constituents such as preservatives,
stabilizers, isotonicizing agents, thickeners, suspension
stabilizers, excipients for pH adjustment, buffer systems and
wetting agents.
Examples of suitable preservatives are: benzalkonium chloride,
chlorobutanol, thiomersal, methylparaben, propylparaben, sorbic
acid and its salts, sodium edetate, phenylethyl alcohol,
chlorhexidine hydro-chloride acetate and digluconate,
cetylpyridinium chloride and bromide, chlorocresol, phenylmercury
acetate, phenylmercury nitrate, phenylmercury borate,
phenoxyethanol.
For preservation, the combination of sodium edetate and
benzalkonium chloride is preferably used. Sodium edetate is
employed here in concentrations of 0.05-0.1% and benzalkonium
chloride in concentrations of 0.005-0.05%. The combination of
sodium edetate, benzalkonium chloride and phenylethyl alcohol is
also preferably employed.
Suitable excipients for the adjustment of the isotonicity of the
formulations are, for example: sodium chloride, potassium chloride,
mannitol, glucose, sorbitol, glycerol, propylene glycol. In
general, these excipients are employed in concentrations from 0.1
to 10%.
The formulations of the invention can also include suitable buffer
systems or other excipients for pH adjustment in order to establish
and maintain a pH of the order of magnitude of 4-8, preferably of 5
to 7.5. Suitable buffer systems are citrate, phosphate, tromethamol
glycine, borate, acetate. These buffer systems can be prepared from
substances such as, citric acid, monosodium phosphate, disodium
phosphate, glycine, boric acid, sodium tetraborate, acetic acid,
sodium acetate. Further excipients can also be used for pH
adjustment, such as hydrochloric acid or sodium hydroxide.
In order to prepare a stable aqueous suspension containing the
water-insoluble active compound loteprednol etabonate, suitable
suspension stabilizers and suitable wetting agents are furthermore
necessary in order to disperse and to stabilize the suspended
active compound in a suitable manner.
Suitable suspension stabilizers are water-soluble or partly
water-soluble polymers: these include, for example, methylcellulose
(MC), sodium carboxymethyl-cellulose (Na-CMC),
hydroxypropylmethylcellulose (HPMC) polyvinyl alcohol (PVAL [sic]),
polyvinylpyrrolidone (PVP), polyacrylic acid, polyacrylamide,
gellan gum (Gelrite.RTM.) hydrated alumina (Unemul.RTM.) dextrins,
cyclodextrins, and mixtures of Microcrystalline cellulose and
sodium carboxymethylcellulose (Avicel RC 501.RTM., Avicel RC
581.RTM., Avicel RC 591.RTM., Avicel CL 611.RTM.). These substances
can simultaneously serve as thickeners in order to increase the
viscosity and thereby to prolong the contact of the active
compounds with the tissue at the application site.
Suitable wetting agents for the formulations are: benzalkonium
chloride, cetylpyridinium chloride, tyloxapol, various polysorbates
(Tween.RTM.), and further polyethoxylated substances and
poloxamers.
EXAMPLES
The following examples illustrate the invention without restricting
it.
Example 1
Nasal spray containing azelastine hydrochloride (0.1%)
TABLE-US-00003 Azelastine hydrochloride 0.1000 g
Hydroxypropylmethylcellulose 0.1000 g Sodium edetate 0.0500 g
Benzalkonium chloride 0.0125 g Sodium hydroxyde q.s. ph 6.0
Sorbitol solution 70% 6.6666 g Purified water to 100 ml
Preparation of the solution
Introduce about 45 kg of purified water into a suitable stirrer
container. Add the active compound, hydroxypropylmethylcellulose,
sodium edetate, benzalkonium chloride and sorbitol solution to this
in succession and dissolve with stirring. Make up the resulting
solution to a volume of 49.5 liters with purified water. Adjust the
pH of the solution to pH 6.0 using 1N sodium hydroxide solution.
Make up to the final volume of 50.0 liters using purified water and
Stir. Filter the solution through a suitable filter and dispense
into bottles which are then provided with a suitable nasal spray
pump.
Example 2
Nasal spray suspension containing loteprednol etabonate (1%)
TABLE-US-00004 Loteprednol etabonate 1.0000 g Avicel RC 591 1.1000
g Polysorbate 80 0.1000 g Sorbitol solution 70% 6.0000 g Sodium
edetate 0.0500 g Benzalkonium chloride 0.0200 g Purified water to
100 ml
Preparation
Introduce 45 kg of purified water into a suitable stirrer container
with a homogenization device and homogenize Avicel RC 591 therein
at high speed. Then dissolve the substances polysorbate 80,
sorbitol solution, sodium edetate and benzalkonium chloride in
succession with stirring. Then homogenize the active compound
loteprednol etabonate at high speed until a uniform suspension is
formed. Then make up to the final volume of 50 liters with purified
water and homogenize further. Then evacuate the suspension in order
to remove the resulting air bubbles. The resulting suspension is
then dispensed into bottles which are then provided with a suitable
nasal spray pump.
Example 3
Nasal spray containing loteprednol etabonate (1%, suspended) and
azelastine hydrochloride (0.1%, dissolved)
TABLE-US-00005 Loteprednol etabonate 1.0000 g Azelastine
hydrochloride 0.1000 g Avicel RC 591 1.1000 g Polysorbate 80 0.1000
g Sorbitol solution 70% 6.0000 g Sodium edetate 0.0500 g
Benzalkonium chloride 0.0200 g Purified water to 100 ml
Preparation
Introduce 45 kg of purified water into a suitable stirrer container
with a homogenization device and homogenize Avicel RC 591 therein
at high speed. Then dissolve the active compound azelastine
hydrochloride and the excipients polysorbate 80, sorbitol solution,
sodium edetate and benzalkonium chloride in succession with
stirring.
Then homogenize the active compound loteprednol etabonate at high
speed until a uniform suspension is formed. Then make up to the
final volume of 50 liters with purified water and homogenize
further. Then evacuate the suspension in order to remove the
resulting air bubbles.
The resulting suspension is then dispensed into bottles which are
then provided with a suitable nasal spray pump.
* * * * *